;G-protein coupled receptors (GPCRs) comprise a large superfamily of target proteins (nearly 800 different human genes encode for GPCRs) and each of them can adopt functionally distinct conformations. New chemotypes and allosteric modulation, which are the focus of this project, will facilitate the development of novel, highly selective drugs because allosteric sites are significantly less conserved between GPCR subtypes and closely related sub-families and display higher structural variation. The Medicinal Chemistry Core will synthesize new GPCR ligands as reagents to enable new crystal structures, as molecular tools to help deconvolute signaling pathways, and as innovative lead compounds. This core aims to provide such optimized molecules, working intimately with all three ofthe Projects. Collaborating with Project 3, the working plan ofthe Medicinal Chemistry Core includes the development of covalent agonists to facilitate high-resolution, active state structures ofthe M2 and MS muscarinic receptors and the synthesis of heavy atom-substituted ligands for structures of muscarinic receptors bound to allosteric modulators. To evaluate effect of allosteric ligands on binding kinetics of purified GPCRs (Project 2), fluorophore-labeled M2 and MS receptor antagonist and agonists will be developed. In the field of ligand discovery and optimization, the Medicinal Chemistry Core will work intimately with Project 1 to optimize new chemotypes identified from library docking campaigns and to develop high affinity allosteric ligands from docking hits, which must be improved by at least two order of magnitude in affinity to become valuable tools and lead compounds for drug discovery. The Medicinal Chemistry Core essentially contributes to the larger project?combining GPCR crystal structure determination with sophisticated new biophysical assays with molecular docking campaigns for new chemotypes.

Public Health Relevance

The Medicinal Chemistry Core will be crucial for the progression of effective and selective allosteric GPCR modulators, which is the long-term goal of this interdisciplinary project. Not only do we expect useful reagents, and occasionally therapeutic leads, to emerge from this program, but also integrated strategies for pragmatic optimization .

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZRG1-BST-J (40))
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Stanford University
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Kruse, Andrew C; Kobilka, Brian K; Gautam, Dinesh et al. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13:549-60
Thorsen, Thor Seneca; Matt, Rachel; Weis, William I et al. (2014) Modified T4 Lysozyme Fusion Proteins Facilitate G Protein-Coupled Receptor Crystallogenesis. Structure 22:1657-64
Kruse, Andrew C; Ring, Aaron M; Manglik, Aashish et al. (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504:101-6